Renal Cell Carcinoma in von Hippel–Lindau Disease—From Tumor Genetics to Novel Therapeutic Strategies

Abstract

von Hippel–Lindau (VHL) disease is an autosomal dominant syndrome caused by mutations in the VHL tumor-suppressor gene, leading to the dysregulation of many hypoxia-induced genes. Affected individuals are at increased risk of developing recurrent and bilateral kidney cysts and dysplastic lesions which may progress to clear cell renal cell carcinoma (ccRCC). Following the eponymous VHL gene inactivation, ccRCCs evolve through additional genetic alterations, resulting in both intratumor and intertumor heterogeneity. Genomic studies have identified frequent mutations in genes involved in epigenetic regulation and phosphoinositide 3-kinase–AKT–mechanistic target of rapamycin (mTOR) pathway activation. Currently, local therapeutic options include nephron-sparing surgery and alternative ablative procedures. For advanced metastatic disease, systemic treatment, including inhibition of vascular endothelial growth factor pathways and mTOR pathways, as well as immunotherapy are available. Multimodal therapy, targeting multiple signaling pathways and/or enhancing the immune response, is currently being investigated. A deeper understanding of the fundamental biology of ccRCC development and progression, as well as the development of novel and targeted therapies will be accelerated by new preclinical models, which will greatly inform the search for clinical biomarkers for diagnosis, prognosis, and response to treatment.

von Hippel-Lindau Syndrome: Genetic Study of Case With a Rare Pathogenic Variant With Optic Nerve Hemangioblastoma, a Rare Phenotypic Expression

“…Additional pathogenic variants for CCRs were found (18), indicating that VHLS-associated neoplasms may not be caused exclusively by pathogenic variants in the VHL gene but also by pathogenic variants in the hypoxia-inducible factor 1-alpha (HIF-1A) gene or in other genes, such as PBRM1, SETD2, and BAP1 (19)(20)(21)(22)(23). The VHL protein participates in the induction and degradation of the HIF-1A protein and in the presence of an anomalous VHL protein, the involvement of VHL in the degradation of HIF-1A is inhibited and proteasomal cleavage is suppressed (23)(24)(25).…”

“…Additional pathogenic variants for CCRs were found (18), indicating that VHLS-associated neoplasms may not be caused exclusively by pathogenic variants in the VHL gene but also by pathogenic variants in the hypoxia-inducible factor 1-alpha (HIF-1A) gene or in other genes, such as PBRM1, SETD2, and BAP1 (19)(20)(21)(22)(23). The VHL protein participates in the induction and degradation of the HIF-1A protein and in the presence of an anomalous VHL protein, the involvement of VHL in the degradation of HIF-1A is inhibited and proteasomal cleavage is suppressed (23)(24)(25). The entry of HIF-1A into the nucleus promotes the transcriptional activation of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF), plateletderived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), chemokine receptor type (CXCR4), erythropoietin (EPO), and glucose transport 1 (GLUT-1) (25), leading to vascular proliferation and angiogenesis, influencing extracellular matrix remodeling, and increasing resistance to apoptosis (26)(27)(28)(29).…”

Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel‑Lindau disease pedigrees

“…However, these treatments cannot be used when the tumor is near the optic nerve, in which case the therapeutic approach is only surveillance, resulting in a high risk of damage to the optic nerve ( 32 ). The average age at diagnosis of VHL-RCC is 39 years (range, 13-70 years) ( 13 , 20 ). VHL-RCC is characterized by simultaneous or heterogeneous bilateral tumors that are multifocal and low grade with a slow progression ( 13 , 20 ).…”

“…The average age at diagnosis of VHL-RCC is 39 years (range, 13-70 years) ( 13 , 20 ). VHL-RCC is characterized by simultaneous or heterogeneous bilateral tumors that are multifocal and low grade with a slow progression ( 13 , 20 ). The metastasis rate of VHL-RCC is very low when tumors are <3 cm and physical therapy, such as waiting for observation or radiofrequency ablation, may be used in clinical treatment ( 13 , 22 ).…”

Neuropilin 1 and Neuropilin 2 Gene Invalidation or Pharmacological Inhibition Reveals Their Relevance for the Treatment of Metastatic Renal Cell Carcinoma

“…Clear cell Renal Cell Carcinoma (ccRCC) is the most common form of kidney cancer representing 90% of all cases [1,2]. If non-metastatic, surgery remains the best treatment.…”